Surgery, a very common and important therapeutic treatment in older adults, frequently induces profound muscle weakness and physical decline in the post-operative period in these vulnerable individuals. Thus, the optimization of peri-operative care is the key to improving surgical outcomes and quality of life in older patients. The proposed K08 project is a critical first step towards meeting this goal. This study will be conducted at the James J. Peters VAMC by Dr. Fred Ko, MD, a junior investigator with training in clinical geriatrics and basic and clinical translational research. This study uniquely focuses on the intersection of aging and muscle biology, surgical stress, and physical activity, and on the strength of animal models, to mechanistically test hypotheses regarding the biology and treatments of post-operative physical decline. In Aim 1, the effects of laparotomy on gastrocnemius muscle biology (IGF-1/IRS/PI3K/Akt and TNF? signaling, muscle protein synthesis) and behavioral phenotype (grip strength, locomotor activity, balance) in the post- operative period of young and aged C57BL/6 mice will be determined utilizing a variety of molecular and cell biology techniques and animal behavioral testing. In Aim 2, the effects of pre-operative treadmill exercise training, post-operative functional blocking TNF? antibody administration, and their combination therapy on gastrocnemius muscle biology and behavioral phenotype will be determined using the same laboratory techniques. It is hypothesized that in aged mice surgery induces post-operative muscle weakness and physical decline by altering IGF-1/IRS/PI3K/Akt and TNF? activity, and that peri-operative interventions with exercise and TNF? blockade attenuate these adverse molecular, muscular, and physical changes. The findings from this project will likely identify candidate molecules that govern, and treatments tha attenuate, post-operative muscle weakness and physical decline. Thus, bench-to-bedside research that stems from this K08 will likely facilitate development of peri-operative strategies that improve surgical outcomes in vulnerable older patients. An integrated career development and mentoring plan has been proposed to ensure this project's successful completion and Dr. Ko's transition to independence. The training goals are centered on Dr. Ko's development of expertise in muscle biology, molecular and cell biology techniques optimized for muscle research, mouse behavioral testing, and his successful competition of an independent research grant within the award period. These goals will be met with rigorous training activities that include formal course work, didactics, seminars, national conferences, and frequent and scheduled meetings with a team of senior scientists. Dr. Ko's scientific and career development will be guided by Christopher Cardozo, MD (primary mentor; muscle biology), Charles Mobbs, PhD (co-mentor; aging biology), Gregory Elder, MD (contributor; behavioral testing), Shalender Bhasin, MD (contributor; exercise intervention), Janice Gabrilove, MD (contributor; biologics), and Joan Penrod, PhD (contributor; statistical methods).